Infantile spasms (IS) are an age-specific epileptic syndrome associated with diverse etiological factors. In recent years, several hypotheses and animal models have been proposed to explain the pathogenesis of IS, but none has elucidated the pathophysiology of IS. In the current case-control study, prenatal stress degree was identified to be higher among the mothers of IS patients than those among the control group. The onset risk of IS increased with the degree of prenatal stress within a certain range. We have recently exposed pregnant rats to forced cold swimming and have given intraperitoneal injection of N-methyl-D-aspartate (NMDA) to rat pups with prenatal stress exposure. Prenatal stress exposure was found to alter the hormonal levels and neurotransmitter receptor expression of developing rats, sensitizing rat pups to develop NMDA-induced spasms and rendering the spasms to be sensitive to adrenocorticotropic hormone therapy. The studies above indicate that prenatal stress plays an important role in the onset of IS. Based on previous hypotheses and the current findings, we propose a prenatal stress exposure hypothesis for IS (also called Zou's hypothesis). (C) 2012 Elsevier Ltd. All rights reserved.